Metabolic syndrome, also known as metabolic syndrome X, cardiometabolic syndrome, syndrome X, and insulin resistance syndrome, is a cluster of medical disorders that, when occurring together, increase the risk of diabetes and cardiovascular disease. See, e.g., Alberti et al. Circulation 2009; 120:1640-1645. Metabolic syndrome affects 35-40% of American adults, and prevalence increases with age. Principal disorders associated with or used in the diagnosis of metabolic syndrome include, but are not limited to, obesity, dyslipidemia, and diabetic conditions, and conditions associated with these disorders, such as elevated glucose levels and hypertension.
Obesity is a risk factor for a wide array of diseases, for example, type 2 diabetes, hypertension, hyperlipidemia, coronary artery disease, stroke, breast and colon cancer, sleep apnea, gall bladder disease, gastroesophogeal reflux disease, fatty liver disease, gout, and thromboembolism. Blood pressure, blood sugar, serum cholesterol, and serum uric acid are usually higher in obese people than in those of normal weight. Despite increased awareness of these health risks, the prevalence of obesity has risen steadily for decades in many industrialized nations. As a result, there has been considerable interest in ways to reduce obesity.
The excess body fat of obese subjects is typically deposited in adipose tissue. This tissue and its principal cell type, the adipocyte, have been implicated in a wide array of diseases, for example, metabolic syndrome, type 2 diabetes, atherosclerosis, fatty liver, hepatic fibrosis, breast cancer, inflammation, depression, and dementia. The causative role of adipose tissue in these diseases appears to involve mediators such as adiponectin, resistin, tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP), fibrinogen, plasminogen activator inhibitor-1 (PAI-1), and/or C-terminal binding protein (CtBP). As a result, the adipocyte per se, rather than being a mere storehouse for calories, plays a pathogenic role in many diseases and represents a target for therapeutic intervention.
A number of medical conditions are considered to be causes of obesity or local excesses of body fat. Examples include drug-induced obesity, hypothyroidism, pseudohypoparathyroidism, hypothalamic obesity, polycystic ovarian disease, depression, binge eating, Prader-Willi syndrome, Bardet-Biedl syndrome, Cohen syndrome, Down syndrome, Turner syndrome, growth hormone deficiency, growth hormone resistance, leptin deficiency or resistance, HIV lipodystrophy, and Cushing syndrome and pseudo-Cushing syndrome (i.e., characteristic syndrome of excess body fat and other findings due to excessive endogenous or exogenous corticosteroid levels). Some of these conditions, for example, Cushing syndrome, pseudo-Cushing syndrome, and HIV-related lipodystrophy, are associated with other features of metabolic syndrome, such as insulin resistance and dyslipidemia.
Medications known to cause obesity or local excess of body fat include cortisol and analogs, other corticosteroids, megace, sulfonylureas, antiretrovirals, tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, oral contraceptives, insulin, risperidone, clozapine, and thiazolidinediones. Some of these medications, for example, corticosteroids and antiretrovirals, are associated with other features of metabolic syndrome, such as insulin resistance and dyslipidemia.
Changes in hormonal status, including physiologic changes such as pregnancy or menopause, may result in obesity in a subject. Smoking cessation commonly leads to weight gain and obesity. Trauma may favor the accumulation of excess body fat by virtue of immobility or disuse of an extremity. Similar problems may affect an immobile subject, such as an astronaut or bedridden subject who is immobilized for an extended period of time. Some tumors, for example, lipomas, are characterized by collections of fat cells that may be amenable to methods to reduce body fat. Even in the absence of underlying pathology, a subject may have cosmetic concerns about body fat. These can usually be attributed to constitutional or hereditary factors, developmental history, age, gender, diet, alcohol use, or other aspects of lifestyle.
A number of methods have been developed to reduce obesity. It is helpful to classify these methods as extractive, metabolic, or adipolytic. Extractive methods, such as lipoplasty (e.g., liposuction) or local excision, are methods whereby fat is physically removed from areas of interest. Such methods do not appear to correct other features of metabolic syndrome. They are costly and may involve scars, postsurgical deformity or regression, discomfort, infection, and other adverse reactions.
In contrast to extractive methods, metabolic methods, which include medications, nutritional supplements, devices, bariatric surgery, and exercise or other body treatment, seek to modify the subject's metabolism (e.g., whether caloric intake, expenditure, or both) such that there is a net loss of fat in the subject. A disadvantage is potential concomitant loss of water, carbohydrates, protein, vitamins, minerals, and other nutrients. Furthermore, traditional diet medications may have undesired side effects, for example, palpitations, tremor, insomnia, and/or irritability in a subject who uses stimulants as appetite suppressants. Drawbacks of surgery are mentioned above. Despite salubrious value, the traditional metabolic methods of diet and exercise are not practical for everybody.
Adipolytic methods aim to cause breakdown of adipocytes and/or their lipid contents. For example, fat deposits can be reduced by exposure to cold temperature or to deoxycholate, a solubilizer which lyses cell membranes and results in local necrosis. Drawbacks of these methods can include poor discrimination between adipose and other nearby tissues, barriers to delivery that require hypodermic needles or special equipment, and adverse effects such as necrosis, inflammation, and pain.
Fat circulates in the blood in various lipid and lipoprotein forms. Common measures of lipid concentration in the blood include serum triglycerides, serum total cholesterol, serum low density lipoprotein (LDL), and serum high density lipoprotein (HDL). These lipid concentrations are heavily influenced by diet and metabolism.
Dyslipidemia is an abnormality in one or more lipid or lipoprotein levels in the blood. Dyslipidemia comprises one or more of: elevated serum triglycerides, elevated total cholesterol, elevated low density lipoprotein (LDL), reduced high density lipoprotein (HDL), and/or abnormal distribution of serum lipoproteins as measured, for example, by nuclear magnetic resonance spectroscopy.
Elevations of some lipid concentrations, e.g. triglycerides and/or LDL, are risk factors for diseases such as atherosclerosis, coronary heart disease, stroke, neurovascular disease, peripheral vascular disease, and diabetes. Conversely, abnormally low levels of HDL are associated with cardiovascular disease. Numerous medications have been developed to treat dyslipidemia, e.g., by reducing lipid and/or lipoprotein concentrations. Of these, the “statins” or HMG CoA reductase inhibitors, which decrease LDL levels, are well known examples. For many patients, however, the currently available therapies are insufficient or unsuitable, for example, due to side effects such as myopathy.
Diabetic conditions include diabetes mellitus and pre-diabetes. Diabetes mellitus, which comprises type 1 diabetes and type 2 diabetes, is a condition characterized by hyperglycemia resulting from the body's inability to use blood glucose for energy. Pre-diabetes is a condition wherein blood glucose levels are higher than normal but not high enough for a diagnosis of diabetes; people with pre-diabetes are at increased risk for developing type 2 diabetes. A common feature of type 2 diabetes and pre-diabetes, insulin resistance, is a physiological condition wherein insulin becomes less effective at lowering blood sugar levels, resulting in elevated blood sugar levels. Impaired glucose tolerance is a condition wherein glucose intake (for example, orally or intravenously) results in abnormally elevated blood sugar levels. Glucose tolerance can be measured, for example, by systematic challenge with an oral glucose load (oral glucose tolerance test). “Diabetic complications” include chronic and acute complications of diabetes. Chronic complications include atherosclerosis, stroke, myocardial ischemia, nephropathy, peripheral neuropathy, retinopathy, infection, foot ulcers, and death. Acute complications include metabolic acidosis, nonketotic hypersosmolar state, volume depletion, coma, and death.
Local reduction of adipose tissue does not treat dyslipidemia or diabetes. The peer-reviewed literature has even expressed concern that lysis of adipocytes could dump lipids into the bloodstream and thereby increase serum lipid concentrations. See, e.g., Klein et al, Lasers Surg Med 2009; 41:785-790. In one clinical trial, local reduction of flank fat by cryolipolysis did not cause any change in serum triglycerides, total cholesterol, LDL, or HDL See, e.g., Klein et al, Lasers Surg Med 2009; 41:785-790. Likewise, local reduction of hip fat by laser lipolysis caused no change in these parameters. See, e.g., Mordon et al, J Cosmet Laser Ther 2009; 11:74-74. Furthermore, surgical removal of subcutaneous fat in hamsters actually increased serum triglyceride levels and insulin resistance due to compensatory deposition of intraabdominal fat. See, e.g., Weber et al, Am J Physiol Regul Integr Comp Physiol 2000; 279:R936-943. Even large-volume lipectomy, which is distinct from local fat reduction, does not consistently elicit a reduction in serum lipids or serum glucose. In one report, 9 of 10 patients who underwent large-volume lipectomy showed reduced serum total cholesterol, but no reduction in triglycerides, or in the HDL:LDL ratio. See, e.g., Baxter, Aesthet Surg J 1997; 17:213-215. Surgical lipectomy in Zucker rats showed mean reductions in serum triglycerides and total cholesterol, but no reductions in serum glucose. See, e.g., Liszka et al, Plast Reconstr Surg 1998; 102:1122-1127.
Even systemic medical therapy for weight loss does not necessarily lead to absolute benefits in serum lipids or glucose. A landmark randomized controlled trial studied the effects of two years of systemic Orlistat therapy in obese adults. See Davidson et al, JAMA 1999; 281:235-243. After two years, subjects randomized to Orlistat 120 mg three times daily lost 8.8% of baseline body weight, compared to 5.8% in the placebo group (p<0.001). However, this weight loss was not accompanied by any absolute improvement in serum lipids or serum glucose.
Therefore, there is a need for new approaches including new methods and compositions for treating and/or preventing metabolic syndrome and associated conditions, for example, treating or preventing obesity, dyslipidemia, and/or diabetic conditions, in a subject in need thereof. These approaches may include reducing fat and/or adipocytes in the subject and optionally also reducing levels of undesired serum lipids and/or serum glucose in the bloodstream.